Experimental Research On Antiangiogenesis Genetherapy Of Bladder Cancer With Human Angiostatin

The formation of new blood vessels occurs as a result of the growth of capillaries by vascular sprouting from preexisting vessels, a process called angiogenesis. Upon growth stimulation, quiescent endothelial cells can enter into the cell cycle, migrate, degrade the underlying basement membrane, and form a lumen. Angiogenesis is required for a variety of physiological processes such as embryonic development, wound healing, and tissue as well as organ regeneration. These processes depend upon the tightly regulated growth of endothelial cells which can be switched on and off within a short period. Abnormal growth of new blood vessels can lead to the progression of many diseases such as diabetic retinopathy and tumor growth. Direct experimental evidence shows that tumor growth and metastases are angiogenesis-dependent. Direct experimental evidences show that solid tumor growth and metastasis require new blood vessels. An avascular tumor (vascular prophase) rarely grows to a size larger than 0.4 mm3 and grows at a slow linear growth speed. Once a tumor becomes vascularized and larger than 0.4 mm3 (vascular phase), the expansion of tumor mass is approximately at an exponential growth rate. Its features are that the tumors grow faster and the cells appear distant metastasis with its vascular bed extention. Therefore, suppressing the tumor angiogenesis and cutting off its nourishment supply can control the tumor growth and metastasis. This treatment strategy is differred from that of antitumor cells. Recent years, antiangiogenesis has become a hot spot study in the tumor treatment. With the development of genetic technology, the combination of antiangiogenesis with gene therapy may be an attractive choice in clinic.Bladder carcinoma is one of commonly seen solid tumors, which badly endangers the people's health and life. Although active surgery treatment accompanied with radiotherapy and chemotherapy were conducted in clinic, but the curative effect is very bad and the mortality is high. So it is urgent to develop a new biological therapy in order to improve the patient's prognosis. At present, there are many kinds of biological treatment plans, such as genetic immunomodulation therapy, immuno-guide therapy, cytokine therapy, tumor vaccine, monoclonal antibody and its interlinkage agents, gene therapy, gene recombinant drugs, tumor apoptosis research, and etc. Because the carcinoma cells have highly heterogenicity and heredity mutability, many biological treatments may cause thedrug resistance and toxic effects, which may affect its curative effects. The endothelial cell proliferation rate determines the tumor cell growth rate. So it has some peculiar advantages in adopting antiangiogenesis methods to treat carcinoma: Endothelial cell is a heredity stable treatment target, rarely mutational, no drug-resistant. Antiangiogenesis has little toxic effects and can be applicable to all kinds of tumors. Some specialists predict that antiangiogenesis treatment should become the most cardinal biological therapy means, but it needs at least several years.There are 30 years in antiangigenesis history. And in recent ten years, a great of progresses have been made in angiogenesis inhibitory factors study.Angiostatin is a circulating angiogenesis inhibitor that has been purified from serum and urine of mice bearing a murine Lewis lung carcinoma, angiostatin contains the first four triple loop disulfide-linked structures of plasminogen, known as kringle domains. In vitro, human angiostatin specifically inhibits endothelial cell proliferation. In vivo, it inhibits neovascularization in the chick chorioallantoic membrane assay and in the mouse corneal assay. At abroard, angiostatin cDNA and its fragments were usually expressed in eukaryotic cells (baculovirus), but the process is very complicated. The yield is so low that it can't satisfied the clinic requirement. In the treatment of tumors, angiostatin and its fragment proteins were usually used, but the using dose is very bigger (the biggest dose to lOOmg/kg) and the application t...